Genetic Variant ENST00000504572.5:c.-13-3185A>G (chr5-143404037-T-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

The ENST00000504572.5(NR3C1):c.-13-3185A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00134 in 985,386 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0054 ( 5 hom., cov: 32)

Exomes 𝑓: 0.00060 ( 6 hom. )

Consequence

NR3C1
ENST00000504572.5 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.309

Publications

4 publications found

Variant links:

Genes affected

NR3C1 (HGNC:7978): (nuclear receptor subfamily 3 group C member 1) This gene encodes glucocorticoid receptor, which can function both as a transcription factor that binds to glucocorticoid response elements in the promoters of glucocorticoid responsive genes to activate their transcription, and as a regulator of other transcription factors. This receptor is typically found in the cytoplasm, but upon ligand binding, is transported into the nucleus. It is involved in inflammatory responses, cellular proliferation, and differentiation in target tissues. Mutations in this gene are associated with generalized glucocorticoid resistance. Alternative splicing of this gene results in transcript variants encoding either the same or different isoforms. Additional isoforms resulting from the use of alternate in-frame translation initiation sites have also been described, and shown to be functional, displaying diverse cytoplasm-to-nucleus trafficking patterns and distinct transcriptional activities (PMID:15866175). [provided by RefSeq, Feb 2011]

NR3C1 Gene-Disease associations (from GenCC):

glucocorticoid resistance
Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Laboratory for Molecular Medicine, Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics

NR3C1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.77).

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00536 (814/151918) while in subpopulation EAS AF = 0.0223 (114/5120). AF 95% confidence interval is 0.0189. There are 5 homozygotes in GnomAd4. There are 409 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 814 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	Protein
NR3C1	NM_001364181.2 link	c.-65A>G	5_prime_UTR_variant	Exon 1 of 9	NP_001351110.1
NR3C1	NM_001364183.2 link	c.-13-3185A>G	intron_variant	Intron 2 of 9	NP_001351112.1
NR3C1	NM_001364184.2 link	c.-14+339A>G	intron_variant	Intron 1 of 8	NP_001351113.1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	Protein	UniProt
NR3C1	ENST00000504572.5 link	c.-13-3185A>G	intron_variant	Intron 2 of 9	1	ENSP00000422518.1	P04150-3
NR3C1	ENST00000503201.1 link	c.-14+339A>G	intron_variant	Intron 1 of 8	1	ENSP00000427672.1	P04150-1
NR3C1	ENST00000502892.5 link	c.-14+582A>G	intron_variant	Intron 1 of 1	1	ENSP00000420856.1	Q3MSN4

Frequencies

GnomAD3 genomes

AF:

0.00531

AC:

806

AN:

151810

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0151

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00183

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0222

Gnomad SAS

AF:

0.00434

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000133

Gnomad OTH

AF:

0.00478

GnomAD4 exome

AF:

0.000605

AC:

504

AN:

833468

Hom.:

Cov.:

AF XY:

0.000561

AC XY:

216

AN XY:

384974

show subpopulations

African (AFR)

AF:

0.0151

AC:

239

AN:

15792

American (AMR)

AF:

0.00101

AC:

AN:

986

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

5154

East Asian (EAS)

AF:

0.0297

AC:

108

AN:

3636

South Asian (SAS)

AF:

0.00133

AC:

AN:

16514

European-Finnish (FIN)

AF:

0.00

AC:

AN:

282

Middle Eastern (MID)

AF:

0.00185

AC:

AN:

1620

European-Non Finnish (NFE)

AF:

0.0000446

AC:

AN:

762168

Other (OTH)

AF:

0.00355

AC:

AN:

27316

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

131

164

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

110

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00536

AC:

814

AN:

151918

Hom.:

Cov.:

AF XY:

0.00551

AC XY:

409

AN XY:

74248

show subpopulations

African (AFR)

AF:

0.0152

AC:

629

AN:

41454

American (AMR)

AF:

0.00183

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3464

East Asian (EAS)

AF:

0.0223

AC:

114

AN:

5120

South Asian (SAS)

AF:

0.00414

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10552

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.000133

AC:

AN:

67904

Other (OTH)

AF:

0.00663

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

125

166

208

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00156

Hom.:

Bravo

AF:

0.00569

Asia WGS

AF:

0.0170

AC:

AN:

3462

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.77

CADD

Benign

(source)

DANN

Benign

0.68

PhyloP100

0.31

PromoterAI

0.082

Neutral

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over